Mild and Chemoselective Carboxylic Acid Reduction Promoted by Borane Catalysis

Abstract Although considerable advances have been made in developing chemoselective transformations of ubiquitous carboxylic acid groups, many challenges still exist. For instance, their selective reduction is problematic if both more nucleophilic and more electrophilic groups are present in the starting material. Here, we address this problem with a simple and mild protocol using bench‐stable reagents at ambient temperatures. This platform is able to tolerate a diverse range of functionality, leaving ketones, esters, nitro‐groups, olefins, nitriles and amides untouched. A combination of experimental and computational mechanistic experiments demonstrate that this reaction proceeds via hidden borane catalysis with small quantities of in situ generated BH3 playing a key role in the exquisite selectivity that is observed.


Materials and Methods
Unless otherwise stated, all reactions were performed with standard Schlenk techniques. All reagents and starting materials were purchased at reagent grade and used as received. Anhydrous solvents were dried using an Innovative Technology PS-MD-5 solvent purification system. Thin layer chromatography (TLC) was performed on Merck Kieselgel 60 F254 aluminum plates with unmodified silica and visualized either under UV light or stained with potassium permanganate, vanillin, or cerium ammonium molybdate (Hanessian's stain). Column chromatography was performed with Merck silica gel 60 (35 -70 mesh). Preparative TLC was performed using pre-coated TLC plates SIL G-50 UV250 (Layer: 0.50 mm silica gel 60 with fluorescent indicator UV250); detection under UV light.

Selected optimizations of reaction conditions
Optimization of the reaction condition was carried out with 4-benzoyl butyric acid 1a on 0.1 mmol scale (Scheme 1).   48  20  -15  EtOAc  62  15  -14  MeCN  56  11  -15  Heptane  48 10 -20 * All the reaction are carried out using 1 mol% of KOtBu and 6 eq of HBpin These data are in agreement with those reported previously in the literature. 1

3-(3-(ethoxycarbonyl)phenyl) propanoic acid (1m)
Prepared following step 2, 1m was obtained after purification by column chromatography (DCM: These data are in agreement with those reported previously in the literature. 2

3-(4-nitrophenyl) propanal (1n')
Prepared following step 1, 1n' was obtained and the crude was used directly in the next step. These data are in agreement with those reported previously in the literature. 3

3-(4-nitrophenyl) propionic acid (1n)
Prepared following step 2, 1n was obtained after purification by column chromatography (DCM: These data are in agreement with those reported previously in the literature. 2

3-(p-cyanophenyl) propionaldehyde (1p')
Prepared following step 1, 1p' was obtained and the crude was used directly in the next step. These data are in agreement with those reported previously in the literature. 4

Synthesis of 3-cyanopropanoic acid (1q)
D-Glutamic acid (441.4 mg, 1 eq, 3 mmol) was dissolved in 1 M aqueous solution of NaOH (1.5 ml). It was treated with trichloroisocyanuric acid (464.8 mg, 0.67 eq, 2 mmol) at room temperature. It was left to stir for 1 h, and the reaction mixture was then treated with 1 M HCl (6 ml), followed by an aqueous solution of 3M HCl (0.1 ml). The crude reaction mixture was extracted with Et2O (2x15 ml), organic layer was washed with water, dried (MgSO4), and the solvent was removed under reduced pressure. Compound 1q was obtained pure in 33% yield (99.9 mg, 1 mmol).

General procedure 1 i. For reactions carried out in THF-d8
In an oven-dried 4 ml vial were introduced starting material (0.1 mmol, 1 eq) and a stirring bar. A cap with rubber septum was used to close the vial and the system was then purged with argon. THF-d8 (c = 1.0 M, 0.1 mL), KO t Bu solution in THF-d8 (c = 0.1 M, 1 mol%, 10 µL) and HBpin (6 eq, 0.6 mmol, 87 µL) were then added successively and the reaction was left to stir at room temperature overnight. After this time, an internal standard (1 eq, 0.1 mmol) and THF-d8 (0.4 ml) were added to the crude reaction mixture to determine the yield by 1 H NMR. The resulting crude was then purified by column chromatography as detailed for the single compounds.

ii. For reactions carried out in 2-MeTHF
In an oven-dried 4 ml vial were introduced starting material (0.1 mmol, 1 eq) and a stirring bar. A cap with rubber septum was used to close the vial and the system was then purged with argon. 2-MeTHF (c = 1.0 M, 0.1 mL), KO t Bu solution in 2-MeTHF (c = 0.1 M, 1 mol%, 10 µL) and HBpin (6 eq, 0.6 mmol, 87 µL) were then added successively and the reaction was left to stir at room temperature overnight. After this time, the solution was diluted with Et2O and washed two times with distilled water. The combined aqueous layers were extracted two times with Et2O and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. An internal standard (1 eq, 0.1 mmol) was added to the crude reaction mixture to determine the yield by 1 H NMR. The resulting crude was then purified by column chromatography as detailed for the single compounds.

Isolations:
In some cases (noted below), separation of the products is difficult due to co-elution of both alcohol and boronic ester with pinacol which is large excess. In these cases, careful selection of eluent is required.

Benzyl alcohol (2d)
Prepared following general procedure 1 (on 0.2 mmol scale, with 7 eq of HBpin, after doing the work-up with 1M aqueous solution of NaOH), 2d was obtained as a colorless oil after purification by column chromatography in 46% yield (10 mg, 92.5 µmol). The isolated yield is significantly lower as a result of difficulties in separation from pinacol.
These data are in close accordance with those previously reported in the literature. 11,12

Reaction scale-up
Naproxen (1.0 g, 1 eq, 4.35 mmol) was weighed into a round bottom flask and this was evacuated and back-filled with Argon. Dry THF (4.35 ml, 1 M) was added and then KOtBu as a 1 M solution in THF (43.5 µl, 1 mol%, 43.5 µmol) and HBpin (3.78 ml, 6 eq, 26.1 mmol). The reaction mixture was left to stir overnight at room temperature. The reaction was quenched with water and extracted with EtOAc (3 x 20 ml). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified by column chromatography (DCM) to obtain a while solid in 57% yield (535.4 mg, 2.47 mmol). The NMR data are in accordance with those reported for compound 2t, and they match those reported previously in the literature. 15

Enantioselectivity of the reaction
Both racemic and (S)-Naproxen (1t) were reduced to the corresponding alcohols (2t-racemic and 2t-(S), respectively) following general procedure 1, and ee was calculated to be 99%. Picture 1 shows HPLC spectrum of the product obtained by reducing racemic naproxen (2tracemic), while Picture 2 shows HPLC spectrum of the product obtained by reducing chiral naproxen (2t-(S)). Picture 3 shows the overlap of the two spectra.

General procedure 2 -Reduction of selected carboxylic acids with stoichiometric BH3·DMS
Conditions A: In an oven-dried 4 ml vial were introduced starting material (0.1 mmol, 1 eq) and a stirring bar. A cap with rubber septum was used to close the vial and the system was then purged with argon. Then, THF (c = 0.5 M, 0.2 mL) was added followed by the addition of BH3·DMS (0.65 ml of prepared 0.2 M solution of BH3·DMS in THF, 1.3 eq, 0.13 mmol) at 0°C. It was left to stir at room temperature during 6 h. The solution was diluted with Et2O and washed two times with distilled water, the combined aqueous layers were extracted two times with Et2O and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. Internal standard (1 eq, 0.1 mmol) was then added to the crude reaction mixture to determine 1 H NMR yield.

Conditions B:
In an oven-dried 4 ml vial were introduced starting material (0.1 mmol, 1 eq) and a stirring bar. A cap with rubber septum was used to close the vial and the system was then purged with argon. Then, THF-d8 (c = 0.5 M, 0.2 mL) was added followed by the addition of BH3·DMS (1.25 ml of prepared 0.2 M solution of BH3·DMS in THF, 2.5 eq, 0.25 mmol) at 0°C. It was left to stir at room temperature during 6 h. After this time, internal standard CHBr3 (1 eq, 0.1 mmol) was added to the crude reaction mixture to determine 1 H NMR yield.
Characterization data for 2n-a: 1  These data are in agreement with those previously. 17
Characterization data for 2p-a: 1  These data are in agreement with those reported previously in the literature. 14

N-(3-hydroxypropyl)benzamide (2r-a)
Prepared following general procedure 2 (conditions A), 2r-a was obtained crude in 43% yield. NMR yield was determined using CHBr3 as the internal standard. These data are in close accordance with those previously reported. 16

Reaction with TMEDA
In an oven-dried 4 ml vial were introduced starting material 1a (0.1 mmol, 1 eq, 19.22 mg) and a stirring bar. A cap with rubber septum was used to close the vial and the system was then purged with argon. 2-MeTHF or THF (c = 1.0 M, 0.1 mL), promoter, HBpin (5 eq, 0.5 mmol, 72.5 µL or 6 eq, 0.6 mmol, 87 µL) and TMEDA (1 eq, 0.1 mmol, 15.1 µL) were then added successively and it was left to stir at room temperature overnight. After this time, the solution was diluted with Et2O and washed two times with distilled water, the combined aqueous layers were extracted two times with Et2O and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum.   The following data was used to plot the graphs in Figure S1. These were obtained by extracting the integrals from Mestrenova and normalising against the internal standard (mesitylene).

NMR monitoring of reduction reactions promoted by borane catalysis
In situ NMR monitoring of the hydroboration reactions were carried out for two substrates: 1b and 1c. These reactions were carried under the optimized conditions (KO t Bu 1 mol%, HBpin 6 eq, THF-d8 1M, under inert atmosphere, over 17 h) on 0.3 mmol scale, using mesitylene (41.6 µl, 1 eq, 0.3 mmol) as the internal standard.
Reaction schemes and stacked spectra are presented below.

Figure S5
: Stacked 13 C NMR spectrum for reduction of 1b

Shielding of the carbonyl peak (δ 174 ppm) is observed in the induction phase of the reaction -consistent with our proposed mechanism.
Compound 1c: Stacked spectra for compound 1c: Figure S6: Stacked 1 H NMR spectrum for reduction of 1c

Similar disappearance of the acidic proton (δ 10.7 ppm) and deshielding of the protons at the α-position to the carboxylic acid peak (δ 2.7 ppm) is observed before product formation.
Figure S7: Stacked 11 B NMR spectrum for reduction of 1c

Figure S8
: Stacked 13 C NMR spectrum for reduction of 1c

Shielding of the carbonyl peak (δ 174 ppm) is observed in the induction phase of the reaction
-consistent with our proposed mechanism. There appear to be diastereomeric intermediates which could correlate to proposed intermediate V.

Computational details
All the Density Functional Theory calculations were carried out using Gaussian16 program package. 18a All the structures were optimized using the B3LYP functional including Grimme empirical dispersion correction with the standard 6-31+G(d) basis set. 18b The nature of stationary points was confirmed by frequency calculations as minima (no imaginary frequencies) or transition states (one imaginary frequency). Transition states were further verified by relaxing the imaginary frequency towards the reactant and the product and doing IRC calculations when needed. In addition, single point calculations using the M062X 6-311++G(3d,2p). Solvation 19

Energy Profiles
Direct hydride insertion from HBpin  Comment: Although HBpin-O t Bu formation is exergonic (Figure S14), the selectivity (Figures S12 & S13) suggest that direct reduction with this species is not a relevant pathway, when comparing to the experimentally observed results. Additionally, these pathways are unlikely, because the low amount of base (1 mol%) means the borohydride species would be formed in only very small quantities and subsequent decomposition to BH3 has been detected experimentally.

XYZ Coordinated and Energies of the Calculated Species
Final free energies are calculated as the sum of E (large basis set: M02-6X) + GCorr..